Signal Transduction Pathways

Abstract

Lithium remains the most widely used treatment for bipolar disorder, and this monovalent cation represents one of psychiatry's most important treatments. Despite its demonstrated efficacy in reducing both the frequency and severity of recurrent affective episodes and decades of clinical use, the molecular mechanisms underlying its therapeutic actions have not fully been elucidated. In this report, we review the exciting recent progress in the identification of key components of signal transduction pathways (in particular, guanine nucleotide-binding proteins [G proteins], adenylyl cyclases, and protein kinase C isozymes) as targets for lithium's actions and attempt to integrate these effects with the large body of data emphasizing alterations in various neurotransmitter (particularly monoaminergic) systems. Regulation of signal transduction within critical regions of the brain by lithium affects the function of multiple neurotransmitter systems and may thus explain lithium's efficacy in protecting susceptible individuals from spontaneous, stress-induced, and drug-induced cyclic affective episodes. Recent evidence has also demonstrated significant effects of lithium on the regulation of gene expression in the central nervous system, effects that may play a major role in the long-term stabilization of mood. The identification of these intracellular targets for lithium's actions offers the potential for the development of novel, improved therapeutic agents and, in conjunction with molecular genetic approaches, may facilitate our understanding of the biological factors predisposing individuals to manic-depressive illness.

Differential display PCR reveals increased expression of 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase by lithium

“…sodium valproate or carbamazepine at therapeutically relevant concentrations [7]). These results add to the growing body of evidence suggesting that lithium alters gene expression in brain after chronic treatment which may be important in its action as a long-term prophylactic treatment for BD [8,9,11]. These results are also consistent with the current notion that psychotropic drug treatment may act through long-term adaptational changes in the CNS to bring about their therapeutic effects [8].…”

“…These latter results suggest that CNPaseII might be a target for CNS signal transduction pathways which regulate protein phosphorylation. Of further interest to this latter possibility is the extensive body of recent data which has suggested that lithium has important effects on such signal transduction pathways [9,11].…”

“…PH S00 1 4-5793(96)0043 3-4 [9,11]. Several studies have demonstrated that lithium alters the expression of the early response gene c-fos through a protein kinase C (PKC)-mediated mechanism [12,13].…”

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment

“…2 Its mode of action is still not firmly established, but an effect on signal transduction pathways has been suggested. [3][4][5] According to the inositol depletion hypothesis, 6,7 lithium works by blocking inositol phosphatases within excessively stimulated neurons. This results in lower levels of myo-inositol and decreases the concentration of phosphatidylinositol, which reduce cellular responses to neurotransmitters.…”

Inositol monophosphatase in immortalized lymphoblastoid cell lines indicates susceptibility to bipolar disorder and response to lithium therapy

“…1 Following the demonstration that therapeutic concentrations of Li uncompetitively inhibit inositol monophosphatase (IMPase) activity, 2 it was proposed 2,3 that this ubiquitous enzyme which regenerates intracellular free inositol is a principal therapeutic target of Li. These considerations spurred us to examine the in vitro activity of IMPase in 106 transformed lymphoblastoid cell lines derived from control subjects and bipolar disorder (BPD) patients characterized by therapeutic response to Li.…”